21-39391828-G-C

Variant names:

• chr21-39391828-G-C
• rs35946782
• NM_004627.6:c.328G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004627.6(GET1):​c.328G>C​(p.Val110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GET1 NM_004627.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.601
• Publications: 6 publications found

Genes affected

GET1 (HGNC:12790): (guided entry of tail-anchored proteins factor 1) This gene is located in the candidate region for congenital heart disease (CHD) in Down syndrome (DS). It encodes a basic protein that functions as a receptor that promotes insertion of tail-anchored proteins in the endoplasmic reticulum membrane. This gene is located at a maternally-methylated differentially methylated region (DMR); however, its transcription may be biallelic, not imprinted. Alternative splicing results in different transcript variants. A pseudogene has been defined on chromosome 4. [provided by RefSeq, Apr 2017]

GET1-SH3BGR (HGNC:54635): (GET1-SH3BGR readthrough) This locus represents naturally occurring readthrough transcription between the neighboring WRB (tryptophan rich basic protein) and SH3BGR (SH3 domain binding glutamate-rich protein) genes on chromosome 21. Readthrough transcripts may encode fusion proteins that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13664865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004627.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	NM_004627.6	MANE Select	c.328G>C	p.Val110Leu	missense	Exon 3 of 5	NP_004618.2
	GET1-SH3BGR	NM_001317744.2		c.328G>C	p.Val110Leu	missense	Exon 3 of 9	NP_001304673.1	A0A3B3ITX9
	GET1-SH3BGR	NM_001350300.2		c.328G>C	p.Val110Leu	missense	Exon 3 of 7	NP_001337229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	ENST00000649170.1	MANE Select	c.328G>C	p.Val110Leu	missense	Exon 3 of 5	ENSP00000496813.1	O00258-1
	GET1-SH3BGR	ENST00000647779.1		c.328G>C	p.Val110Leu	missense	Exon 3 of 9	ENSP00000497977.1	A0A3B3ITX9
	GET1	ENST00000380708.5	TSL:1	c.226G>C	p.Val76Leu	missense	Exon 3 of 5	ENSP00000370084.1	O00258-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 51

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.8
DANN	Benign	0.88
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.60
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.14
Sift	Benign	0.062	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.44
MutPred		0.61		Loss of catalytic residue at V110 (P = 0.0082)
MVP		0.030
MPC		0.38
ClinPred		0.14	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.54
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35946782; hg19: chr21-40763754;